Synthesis method of 6-bromo-1, 4, 4-trimethyl-1, 2, 3, 4-tetrahydroquinoline
A high-yield, high-purity 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline was successfully prepared via amidation, acylation, and boron dimethyl sulfide reaction, solving the problem of insufficient production methods in existing technologies.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-27
- Publication Date
- 2026-03-27
AI Technical Summary
There is a lack of existing technologies for producing 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline with high yield.
6-Bromo-1,4,4-Trimethyl-1,2,3,4-Tetrahydroquinoline was prepared by amidation of 4-bromoaniline with 3-methylbut-2-enoyl chloride, followed by reaction with aluminum trichloride, then mixing with potassium hydroxide and potassium iodide, and finally reacting with borane dimethyl sulfide.
A high-yield and high-purity preparation of 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline was achieved, and the process is simple and easy to operate.
Abstract
Description
Technical Field
[0001] This invention belongs to the field of chemical technology, specifically relating to a method for synthesizing 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline. Background Technology
[0002] Tetrahydroquinolines are a class of chemical substances, belonging to the derivatives of quinolines, obtained by hydrogenating some or all of the carbon-carbon double bonds on the quinoline ring. There are many types of tetrahydroquinoline derivatives, including but not limited to 5,6,7,8-tetrahydroquinoline, 4-chloro-5,6,7,8-tetrahydroquinoline, and 1-methyl-1,2,3,4-tetrahydroquinoline-6-carboxaldehyde. These compounds have different physicochemical properties and applications.
[0003] 6-Bromo-1,4,4-Trimethyl-1,2,3,4-Tetrahydroquinoline is a derivative of tetrahydroquinoline, and its applications are mainly concentrated in organic synthesis and pharmaceuticals. This compound plays an important role in chemical synthesis due to its specific chemical structure and properties. However, currently, there is no method for producing 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline in high yield. Summary of the Invention
[0004] To address the aforementioned technical problems, this invention provides a method for synthesizing 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline with high yield and easy production.
[0005] To solve this technical problem, the technical solution of the present invention is as follows: A method for synthesizing 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline, the method comprising the following steps: (1) 4-Bromoaniline and 3-methylbut-2-enoyl chloride were subjected to an amidation reaction in a solvent to obtain 3-methylbut-2-enoic acid (4-bromophenyl)-amide; ; The structural formula of 3-methylbut-2-enoyl chloride is: ; (2) 3-methyl-but-2-enoic acid (4-bromophenyl)-amide was reacted in the presence of aluminum trichloride to obtain 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one; ; (3) Mix 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one, potassium hydroxide, potassium iodide and dimethyl sulfoxide, and react to obtain 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one; ; (4) 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one was reacted with boron dimethyl sulfide to obtain 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline; .
[0006] In some embodiments, step (1) involves taking 4-bromoaniline, 3-methylbut-2-enoyl chloride, and triethylamine in a mass ratio of 25-35:17-26:145, mixing 4-bromoaniline, triethylamine, and solvent DCM evenly, adding 3-methylbut-2-enoyl chloride at -1 to 2°C, heating to 25-35°C, and reacting to obtain 3-methyl-but-2-enoic acid (4-bromophenyl)-amide.
[0007] In some embodiments, step (2) involves taking 3-methyl-but-2-enoic acid (4-bromophenyl)-amide and aluminum trichloride at a mass ratio of 35-43:82-88, mixing aluminum trichloride and solvent DCM evenly, adding 3-methyl-but-2-enoic acid (4-bromophenyl)-amide at -1-2°C, heating to 25-35°C, and reacting to obtain 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one.
[0008] In some embodiments, step (3) involves taking 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one, potassium iodide, and potassium hydroxide in a mass ratio of 6:6 to 11:2, mixing potassium hydroxide with solvent DMSO, adding 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one at -1 to 2°C, heating to 25 to 35°C, stirring, cooling to -1 to 2°C, adding iodomethane, heating to 25 to 35°C, and reacting to obtain 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one.
[0009] In some embodiments, step (4) involves taking 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one and boron dimethyl sulfide at a solid-liquid ratio of 6:2 to 5 g / mL, mixing 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one, boron dimethyl sulfide, and toluene evenly, heating to 105 to 115°C under nitrogen protection, and reacting to obtain 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline. Beneficial effects
[0010] This invention yields 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline via amidation and acylation reactions using 4-bromoaniline as a starting material. The process of this invention is simple, easy to operate, and produces products with high yield and high purity. Detailed Implementation
[0011] Unless otherwise specified, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of any discrepancy, the definitions in this specification shall prevail.
[0012] Unless otherwise stated, all percentages, portions, proportions, etc. are by weight.
[0013] The terms “comprising,” “including,” “having,” “containing,” “or any other variation thereof” as used herein are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to those elements, but may also include elements not expressly listed or other elements inherent to such composition, process, method, article, or apparatus.
[0014] When quantities, parts by weight, or other numerical values or parameters are given as ranges, preferred ranges, or a series of upper and lower preferred values, it should be understood that they specifically disclose all ranges formed by any pair of values of any larger or preferred range limit and any smaller or preferred range limit, regardless of whether the ranges are disclosed separately. For example, when describing a range of "1 to 5", the described range should be understood to include ranges such as "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. Unless otherwise stated, where numerical ranges are described herein, the range is intended to include the range endpoints as well as all integers, fractions, decimals, etc., within that range.
[0015] Furthermore, the indefinite articles “a” and “an” preceding the elements or components of this disclosure are intended to indicate that there is no limitation on the number of times the said element or component appears (i.e., occurs). Therefore, “a” or “an” should be understood to include one or at least one, and unless the quantity is explicitly stated to be singular, the singular form of the said element or component also includes the plural case.
[0016] Unless otherwise specified, the materials, methods, and examples described herein are exemplary and not limiting. While similar or equivalent methods and materials may be used in implementing or testing this disclosure, suitable methods and materials are also described herein.
[0017] Yield calculation formula: (Product mass: Product molecular weight) / (Raw material mass: Raw material molecular weight).
[0018] This disclosure is described in detail below. Example 1
[0019] A method for synthesizing 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline, the method comprising the following steps: (1) 25g of 4-bromoaniline, 145g of triethylamine and 300mL of solvent DCM were mixed evenly. 17g of 3-methylbut-2-enoyl chloride was added at -1℃. The temperature was raised to 25℃ and the reaction was carried out for 16h. The reaction was detected by TLC. After the reaction was completed, 200mL of saturated sodium bicarbonate was added to the reaction solution and stirred for 15min. The solution was separated and the organic phase was concentrated to obtain 36g of 3-methyl-but-2-enoic acid (4-bromophenyl)-amide. The yield was 97.5% and the purity was 98.7%. (2) Mix 82g of aluminum trichloride and 500mL of solvent DCM evenly, add 35g of 3-methyl-but-2-enoic acid (4-bromophenyl)-amide at -1℃, heat to 25℃, react for 6h, and detect by TLC. After the reaction of the raw materials is completed, pour the reaction solution into ice water (500mL), extract with dichloromethane (500 mL *2), concentrate the organic phase, add MTBE (200 mL) to the residue, stir for 30min, filter, dry the filter cake, and obtain 27g of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one, with a yield of 77.1% and a purity of 97.3%. (3) Mix 2g of potassium hydroxide and 100mL of solvent DMSO. Add 6g of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one at -1℃, heat to 25℃, stir for 1h, cool to -1℃, add 6g of iodomethane, heat to 25℃, react for 15h, and detect by TLC. The reaction of the raw materials is complete. Add 200mL of water to the reaction solution, extract with ethyl acetate (150 mL * 2), concentrate the organic phase, and obtain 6.2g of 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one. The yield is 97.9% and the purity is 97.8%. (4) Mix 6g of 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one, 2mL of boron dimethyl sulfide, and 100mL of toluene until homogeneous. Under nitrogen protection, heat to 105℃ and react for 5h. TLC detection indicates that the reaction of the starting material is complete. Pour the reaction solution into ice water (100mL), extract with ethyl acetate (100mL*2), concentrate the organic phase, stir with silica gel, pass through a column with a mobile phase of n-hexane / ethyl acetate = 20 / 1, collect the target spot, concentrate, and obtain 5.4g of 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline with a yield of 95% and a purity of 97.9%. Example 2
[0020] A method for synthesizing 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline, the method comprising the following steps: (1) 28g of 4-bromoaniline, 145g of triethylamine and 300mL of solvent DCM were mixed evenly. 20g of 3-methylbut-2-enoyl chloride was added at 0℃. The temperature was raised to 28℃ and the reaction was carried out for 16h. The reaction was detected by TLC. After the reaction was completed, 200mL of saturated sodium bicarbonate was added to the reaction solution and stirred for 15min. The solution was separated and the organic phase was concentrated to obtain 43g of 3-methyl-but-2-enoic acid (4-bromophenyl)-amide. The yield was 100% and the purity was 98.8%. (2) Mix 85g of aluminum trichloride and 500mL of solvent DCM evenly, add 38g of 3-methyl-but-2-enoic acid (4-bromophenyl)-amide at 0℃, heat to 29℃, react for 6h, and detect by TLC. After the reaction of the raw materials is completed, pour the reaction solution into ice water (500mL), extract with dichloromethane (500 mL *2), concentrate the organic phase, add MTBE (200 mL) to the residue, stir for 30min, filter, dry the filter cake, and get 31g of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one. The yield is 81.6% and the purity is 98.3%. (3) Mix 2g of potassium hydroxide and 100mL of solvent DMSO. Add 6g of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one at 0℃, heat to 29℃, stir for 1h, cool to 0℃, add 8g of iodomethane, heat to 28℃, and react for 15h. Detect by TLC, and the reaction is complete. Add 200mL of water to the reaction solution, extract with ethyl acetate (150 mL * 2), concentrate the organic phase, and obtain 6.3g of 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one with a yield of 99.5% and a purity of 98.2%. (4) Mix 6g of 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one, 3mL of boron dimethyl sulfide, and 100mL of toluene until homogeneous. Under nitrogen protection, heat to 108℃ and react for 5h. TLC detection indicates that the reaction of the starting material is complete. Pour the reaction solution into ice water (100mL), extract with ethyl acetate (100mL *2), concentrate the organic phase, stir with silica gel, pass through a column with a mobile phase of n-hexane / ethyl acetate = 20 / 1, collect the target spot, concentrate, and obtain 5.5g of 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline with a yield of 96.7% and a purity of 98.1%. Example 3
[0021] A method for synthesizing 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline, the method comprising the following steps: (1) 33g of 4-bromoaniline, 145g of triethylamine and 300mL of solvent DCM were mixed evenly. 24g of 3-methylbut-2-enoyl chloride was added at 0℃. The temperature was raised to 32℃ and the reaction was carried out for 16h. The reaction was detected by TLC. After the reaction was completed, 200mL of saturated sodium bicarbonate was added to the reaction solution and stirred for 15min. The solution was separated and the organic phase was concentrated to obtain 49g of 3-methyl-but-2-enoic acid (4-bromophenyl)-amide. The yield was 100% and the purity was 99.1%. (2) Mix 86g of aluminum trichloride and 500mL of solvent DCM evenly, add 40g of 3-methyl-but-2-enoic acid (4-bromophenyl)-amide at 0℃, heat to 33℃, react for 6h, detect by TLC, after the raw material reaction is complete, pour the reaction solution into ice water (500mL), extract with dichloromethane (500 mL *2), concentrate the organic phase, add MTBE (200 mL) to the residue, stir for 30min, filter, dry the filter cake, and obtain 35g of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one, with a yield of 87.5% and a purity of 98.9%; (3) Mix 2g of potassium hydroxide and 100mL of solvent DMSO. Add 6g of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one at 0℃, heat to 33℃, stir for 1h, cool to 0℃, add 9g of iodomethane, heat to 33℃, react for 15h, and detect by TLC. The reaction of the raw materials is complete. Add 200mL of water to the reaction solution, extract with ethyl acetate (150 mL * 2), concentrate the organic phase, and obtain 6.5g of 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one. The yield is 100% and the purity is 97.1%. (4) Mix 6g of 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one, 4mL of boron dimethyl sulfide, and 100mL of toluene until homogeneous. Under nitrogen protection, heat to 113℃ and react for 5h. TLC detection indicates that the reaction of the starting material is complete. Pour the reaction solution into ice water (100mL), extract with ethyl acetate (100mL*2), concentrate the organic phase, stir with silica gel, pass through a column with a mobile phase of n-hexane / ethyl acetate = 20 / 1, collect the target spot, concentrate, and obtain 5.6g of 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline with a yield of 98.5% and a purity of 98.3%. Example 4
[0022] A method for synthesizing 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline, the method comprising the following steps: (1) Mix 35g of 4-bromoaniline, 145g of triethylamine and 300mL of solvent DCM evenly, add 26g of 3-methylbut-2-enoyl chloride at 2℃, heat to 35℃ and react for 16h. After the reaction of the raw materials is completed by TLC, add 200mL of saturated sodium bicarbonate to the reaction solution, stir for 15min, separate the liquid and concentrate the organic phase to obtain 51g of 3-methyl-but-2-enoic acid (4-bromophenyl)-amide, with a yield of 98.6% and a purity of 97.3%. (2) Mix 88g of aluminum trichloride and 500mL of solvent DCM evenly, add 43g of 3-methyl-but-2-enoic acid (4-bromophenyl)-amide at 2℃, heat to 35℃, react for 6h, detect by TLC, after the raw material reaction is complete, pour the reaction solution into ice water (500mL), extract with dichloromethane (500 mL *2), concentrate the organic phase, add MTBE (200 mL) to the residue, stir for 30min, filter, dry the filter cake, and get 30g of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one, with a yield of 69.8% and a purity of 93.6%; (3) Mix 2g of potassium hydroxide and 100mL of solvent DMSO. Add 6g of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one at 2℃. Heat to 35℃ and stir for 1h. Cool to 2℃ and add 11g of iodomethane. Heat to 35℃ and react for 15h. Detect by TLC. The reaction of the raw materials is complete. Add 200mL of water to the reaction solution and extract with ethyl acetate (150 mL * 2). Concentrate the organic phase to obtain 6g of 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one. The yield is 94.8% and the purity is 95.3%. (4) Mix 6g of 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinoline-2-one, 5mL of boron dimethyl sulfide, and 100mL of toluene evenly, under nitrogen protection, heat to 115℃ and react for 5h. Detect by TLC. After the reaction is complete, pour the reaction solution into ice water (100mL), extract with ethyl acetate (100mL*2), concentrate the organic phase, stir with silica gel, pass through a column, mobile phase: n-hexane / ethyl acetate = 20 / 1, collect the target point, concentrate, and obtain 4.9g of 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline, with a yield of 86.2% and a purity of 93.9%.
[0023] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for the synthesis of 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline, characterized in that, The synthesis method comprises the following steps: (1) acylating 4-bromoaniline with 3-methylbut-2-enoyl chloride in a solvent to obtain 3-methyl-but-2-enoic acid (4-bromophenyl) amide; (2) reacting 3-methyl-but-2-enoic acid (4-bromophenyl) amide under the action of aluminum chloride to obtain 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one; (3) mixing 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one, potassium hydroxide, potassium iodide and dimethyl sulfoxide, and reacting to obtain 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one; (4) reacting 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one with borane dimethyl sulfide to obtain 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline.
2. The process for the synthesis of 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline according to claim 1, characterized in that, In step (1), 4-bromoaniline, 3-methylbut-2-enoyl chloride and triethylamine are mixed in a mass ratio of 25-35:17-26:145, 4-bromoaniline and triethylamine are uniformly mixed with a solvent DCM, 3-methylbut-2-enoyl chloride is added at-1-2℃, the temperature is raised to 25-35℃, and 3-methyl-but-2-enoic acid (4-bromophenyl) amide is obtained by reaction.
3. The process for the synthesis of 6-bromo-1,4,4-trimethyl-1,2,3,4- tetrahydroquinoline according to claim 1, characterized in that, In step (2), 3-methyl-but-2-enoic acid (4-bromophenyl) amide and aluminum chloride are mixed in a mass ratio of 35-43:82-88, aluminum chloride and a solvent DCM are uniformly mixed, 3-methyl-but-2-enoic acid (4-bromophenyl) amide is added at-1-2℃, the temperature is raised to 25-35℃, and 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one is obtained by reaction.
4. The process for the synthesis of 6-bromo-1,4,4-trimethyl-1,2,3,4- tetrahydroquinoline according to claim 1, characterized in that, In step (3), 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one, potassium iodide and potassium hydroxide are mixed in a mass ratio of 6:6-11:2, potassium hydroxide and a solvent DMSO are mixed, 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one is added at-1-2℃, the temperature is raised to 25-35℃, stirring is performed, the temperature is lowered to-1-2℃, methyl iodide is added, the temperature is raised to 25-35℃, and 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one is obtained by reaction.
5. The process for the synthesis of 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline according to claim 1, characterized in that, In step (4), 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one and borane dimethyl sulfide are mixed in a solid-liquid ratio g / mL of 6:2-5, 6-bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one, borane dimethyl sulfide and toluene are uniformly mixed, nitrogen protection is performed, the temperature is raised to 105-115℃, and 6-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline is obtained by reaction.